Products for rendering the urine bacteriostatic



. Patented Dec. 7, 1937 UNlTED STATES PATENT OFFICE PRODUCTS ron RENDERING 'rnn 'mnm inao'rnmos'rnrio Theodore H- Rider, Marlemont, and Robert Shelton and John Haynes, Cincinnati, Ohio, assignors to The Wm. S. Merrell Company, Gincinnati, Ohio, a corporation of Ohio No Drawing.

8 Claims.

Another object is to provide products of this.

1& improved 'aracter that can be used therapeutically b to support a full ketogenic diet in cases wherein the diet alone is incompletely'eflective and also in conjunction with a modified ketogenic diet, thus making-it possible 'for the physician to go more certainly render the urine bacteriostatic in patients who are not hospitalized and whose diet therefore cannot be absolutely controlled.

These and other objects are attained by the means herein fully set forth in the following 25 specification.

It has been rather widely recognized in recent years that the commonly used and so-called urinary antiseptics are of questionable value in a sizable percentage ofcases and that the use of the 30 so-called ketogenic diet has given results which are statistically more favorable. It is thecommon understanding 'atthe present time that the ketogenic diet renders urinebacteriostatic, when it does, bycausing an imperfect metabolic dis- 1 35 posal of the decomposition products of fats with the. resultant excretion of levo beta hydroxybutyric acid in the urine. The bacteriostatic 'activity of such urine is attributed to the levo beta hydroxybutyric acid content, and to concomitant acidity.

A fair'number of clinical cases are resistant to the eflccts of the'ketogenic diet when used as such, that is, the diet alone is not sufllcient to render the urine bacteriostatic. Furthermore; it

45 is deemed desirable, if possible, to obviate the necessity of a strictly ketogenic diet; It has been noted that the oral administration of hydroxybutyric acid aids in increasing. the quantity of levo hydroxybutyric acid in the urine. The

only hydroxybutyric acid available-generally is the racemic form and when this is administered orally the dextro-isomer appears to be completely decomposed and therefore to be of no value. The oral administration, therefore, of levo hydrox'y, butyric acid would be sufllcient were it not for the Application July 26, 1934, SerialNo. 787,102-

fact that this product would be difllcult and expensive to obtain in a form suitable for administration. It has been experimentally shown and recorded that certain other products when administered orally result in the excretion of levo hydroxybutyric acid in the urine. Outstanding among these products is-aceto acetic acid; and other acids to which-have beenattributed like .effect are butyric, crotonic. phenylbutyric, isovaleric, and valeric acids.

In the case ofaceto acetic acid there are several objections to its medical use. These are primarily its relatively high toxicity, its relatively great instability and the undesirable side effects of administration such as nausea, vomiting, gastric'irrita'tion, etc. On the other hand, aceto acetic acid'has the supposed benefits of being more or less quantitatively converted by the animal body into levo hydroxybutyric acid.

The inventors herein have discovered that esters of these acids may be administered with much less objectionable side reaction than the acids themselves andthat the esters are fully as satisfactory from the view point of production of ketone bodies in the urine. For various reasons, including. economy,-ethyl aceto acetate is at presmt conceived to be the preferred product for medicinal .use although the invention is not to be considered limited to this one product. The

inventors realize that all simple esters, such as A the esters of aliphatic alcohols, mono-, di-, and

I tri 'hydric, and the esters of'subst-ituted alcohols, such as benzyl alcohol would give approximately equivalent results therapeutically provided only that thealcohol used-in preparing theester had no objectionable physiological eflect in itself.

'- Experimental work in the laboratory and clinic has shown that ethyl aceto acetate is less toxic than hydroxybutyric acid or aceto acetic acid and that it can be administered, preferably enclosed v49 in soft gelatin capsules, in sumcient dose to render the urine bactertiostatic, without toxic symptoms or other .deleterious side effects. .The product can be used therapeutically both to support a full ketogenic diet in cases in which such A diet alone is incompletely effective and also in conjunction with a modified ketogenic diet, making it possible for the" physician to more certainly render the urine bacteriostatic in patients who are not hospitalized and whose diet therefore A cannot be absolutely governed. An additional advantage of the therapeutic-use of ethyl aceto acetate is the fact that clinical results indicate that it aids in rendering or maintaining the urine at-a suflicient degreeof acidity to allow the full bacteriostatic effect of the acetone bodies excreted.

While ethyl acetoacetate is at present conceived to be the preferred product, we have also demonstrated that a variety of esters as described ofthis andr-the othergacids specified do have similar qualitative.. properties. Particularly worthy of mention are the esters of beta hydroxybutyric acid. The mixed esters of the: racemic acid are easily prepared and are therapeutically active. The esters of the levo hydro'xybut-yric acid would be preferred to the' mixed esters of the racemic acid but-cannot be prepared so economically. Following the administration of any of these esters it is our-belief that the resultant bacteriostatic eflect in the urine is due to beta hydroxybutyric acid. It is not inconceivable, however, that in some of these cases at least, particularly following the administration,

of the esters of butyric, crotonic, phenylbutyric, iso-valeric, and valeric acids, that other products which would fall into the broad classification of ketone bodies might beexcreted and active as baoteriostatic agents.

The claims, therefore, rena: to be considered 7 product has been found clinically to be well tolerated in doses of two (2) grams and-it has been further demonstrated that smaller doses have produced a definite secretion of acetone 40 bodies inthe urine in the same day as administered even without the concomitant use of the .ketogenic diet.

What is claimed is:

1. A therapeutic agent for oral administration for rendering the urine bacteriostatic comprising the esters of those simple organic acids selected from the group consisting of aceto acetic acid, hydroxy-butyric acid, butyric acid, phenol butyric acid, valeric acid, iso-valeric acid and crotonic acid, the administration of which acids is known to cause the excretion of acetone bodies in the urine when administered as acids.

2. A therapeutic agent for rendering the urine bacteriostatic consisting of the esters of aceto acetic acid.

3. A therapeutic agent for rendering the urine bacteriostaticcomprising the esters of hydroxybutyric acid.

4. A therapeutic agent for oral administration 'for producing ketosis of desired grade comprising the esters of simple organic-acids selected from the group. of acids which when administered as acids are known to ordinarily effect ketonuri following their administration.

5. A therapeutic agent for oral administration for use in cases wherein ketosis of desired grade is required comprising ethyl aceto acetate- 6, A therapeutic agent for rendering the urine bacteriostatic consisting of the esters of betahydroxybutyric acid. Q I

7. A therapeutic agent for rendering the urine bacteriostatic consisting of beta-hydroxybutyric acid ethyl ester.

8. Atherapeutic agent for oral administration for use in producing ketosis of desired degree comprising encapsulated dosage quantities of ethyl aceto-acetic acid.

' THEODORE H. RIDER.

ROBERT SHELTON. JOHN HAYNES. 

